Phosphorylated TDP-43 in Muscle as a Biomarker for ALS

TDP-43 is one of the proteins more recently discovered to become phosphorylated and form harmful aggregates in aged tissues. These aggregates are connected to a range of neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS). Researchers here discuss a novel way to use TDP-43 as a biomarker for the early onset of ALS. Being able to quantify the progression of neurodegenerative conditions in their early stages is a necessary part of the development of effective means of prevention.

Clinicians diagnose ALS based on deteriorating motor function, such as weakness in the arms or legs or difficulty walking. Motor neurons in the brain and spinal cord of people with ALS contain cytoplasmic inclusions of TDP-43, but currently, these can only be detected after a person has died. Recently, other researchers had looked for TDP-43 in muscle biopsies from three cases, spotting inclusions within intramuscular nerve bundles.

To see if this held true in a larger sample, researchers analyzed bicep, quadricep, diaphragm, or tongue muscles postmortem from 10 sporadic ALS cases and 12 age- and sex-matched controls. Within the tissue, they saw intramuscular nerves that had atrophied and puncta of phosphorylated TDP-43 in nerve axons. Neither occurred in the control tissue. Hyperphosphorylated TDP-43 forms aggregates in ALS and other neurodegenerative diseases. The findings suggest that TDP-43 inclusions within muscle tissue could become a marker for late-stage ALS.

What about early stage disease? Researchers analyzed muscle biopsies taken from adults who were experiencing muscle weakness. Of the available biopsies from 114 participants, 71 had captured intramuscular nerve bundles. Of these samples, 33 contained TDP-43 inclusions in nerve axons. All 33 volunteers were subsequently diagnosed with ALS an average of five months after biopsy. Of the 38 participants whose biopsies contained nerve bundles but no TDP-43 inclusions, none developed ALS; rather, all were later diagnosed with a different neurodegenerative disease, such as spinal muscular atrophy.


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